“The next big thing” in diabetes: clinical progress on DPP‐IV inhibitors

Inhibitors of the enzyme dipeptidyl peptidase‐IV (DPP‐IV) appear poised to become the next major advance in the treatment of type 2 diabetes mellitus (T2DM). Glucagon‐like peptide‐1 (GLP‐1) is an “incretin hormone” released from L cells in the small intestine in response to the ingestion of nutrients, which enhances the glucose‐dependent secretion of insulin from pancreatic β‐cells. In type 2 diabetic patients, the continuous infusion of GLP‐1 decreases plasma glucose and hemoglobin A 1c concentrations and improves β‐cell function. The rapid clearance of active GLP‐1 (in vivo half‐life ∼1 min) through DPP‐IV processing poses challenges to the development of exogenous GLP‐1‐based therapy. The inhibition of endogenous GLP‐1 degradation by reducing DPP‐IV activity is an alternative strategy for improving the incretin action of GLP‐1 in vivo. The area has attracted increasing attention in recent years from both academic and pharma researchers. Numerous reports of small‐molecule DPP‐IV inhibitors have appeared in the recent literature; many more reports describe the beneficial effects of these inhibitors in vitro and in animal models of T2DM. More recently, this approach has been explored clinically, with the most advanced agents currently under review by regulators. This review highlights the progress and status of clinically evaluated agents of this class, also noting key preclinical experiments that have provided proof of concept for this novel mechanism of action. Drug Dev. Res. 67:627–642, 2006.